The broad objectives of this proposal are to elucidate the mechanisms that promote stability and change within vertebrate genomes. This knowledge is critical for understanding how the integrity of information encoded in the human genome is maintained and passed from cell to cell. Disruption of the numerous mechanisms that participate in the maintenance of genome structure is the root cause of many types of cancers and other genomic disorders. Many complimentary systems will need to be developed in order to more fully appreciate the diversity of mechanisms that participate in the maintenance of genome integrity, and mediate the rearrangement of DNA sequences. Indeed, the NIH has recognized the importance of developing non-mammalian model systems for comparative and functional genomic studies. The sea lamprey (Petromyzon marinus) is emerging as an attractive system for understanding the fundaments of vertebrate biology and was chosen by the NIH and NHGRI for whole genome sequencing, in order to facilitate further research using this important vertebrate lineage. This proposal builds on recently experimental developments that reveal the lamprey's novel genome biology. The lamprey undergoes dramatic changes in the architecture of its genome that occur as a feature of its normal development. This results in a situation wherein nearly every somatic tissue possesses a genome that is dramatically different from its germline precursor (i.e.sperm). These rearrangements occur at a massive (genome-wide) scale, are highly predictable, and are regulated during normal development. The specific aims of this proposal are to expand this newly discovered information about the lamprey genome such that we can begin to understand the molecular causes and consequences of these rearrangements in lamprey and ultimately translate these into a better understanding of the mechanisms by which rearrangements of the human genome are and can be regulated. LAY SUMMARY: Tight maintenance of genome structure is critical for maintenance of health and survival. Some exceptional species undergo dramatic changes in their genome structure that mimic disease causing changes. Proposed research is targeted at the genome of one of these species (the sea lamprey) and strives to better understand how such dramatic changes are regulated and affect the biology of this non- human model of basal vertebrate development.